Table 1.

Action potential characteristics and cardiac phenotype of HCN4 mouse models

Reference	Firing properties (single cells)	Membrane potential (MDP/RMP)	Firing frequency (single cells)	Heart rate (HR)	Cardiac phenotype
HCN4 knockout
Stieber et al. [66] HCN4 knockout Global	Not reported	Not reported	Not reported	Not reported	Embryonic lethality
Stieber et al. [66] HCN4 knockout Heart-specific	Isolated embryonic cardiomyocytes: Immature pacemaker potentials	Unchanged KO: − 65 mV WT: − 70 mV	Isolated embryonic cardiomyocytes: Firing rate normal	Isolated embryonic hearts: HR reduced	Embryonic lethality Isolated embryonic hearts: Chronotropic effect absent
Herrmann et al. [29] HCN4 knockout Global Tamoxifen-inducible	Isolated SAN cells: Large fraction of quiescent cells (90%)	Hyperpolarized Δ =  − 8 mV	Spontaneously active cells: Firing rate normal	Adult mice: HR unchanged	Sinus pauses Chronotropic effect preserved
Hoesl et al. [33] HCN4 knockout Conduction system-specific	Isolated SAN cells: large fraction of quiescent cells	Hyperpolarized	Spontaneously active cells: Firing rate normal	Adult mice: HR unchanged	Sinus pauses Chronotropic effect preserved
Baruscotti et al. [3] HCN4 knockout Heart-specific Tamoxifen-inducible	Isolated SAN cells: Successive reduction in firing frequency after induction of KO	Not reported	Isolated SAN cells: Firing rate reduced	Adult mice: HR reduced	Bradycardia, AV block, sinus arrest Chronotropic effect preserved
Mesirca et al. [52] hHCN4-AYA (transgenic, dominant-negative) Heart-specific Inducible (doxycycline-withdrawal)	Isolated SAN cells: Delayed after depolarizations (DADs)	Unchanged Mutant: − 64 mV WT: − 60 mV	Isolated SAN cells: Firing rate reduced	Adult mice: HR reduced	Bradycardia, AV block, ventricular tachycardia Chronotropic effect preserved
HCN4 overexpression or knockdown
Kozasa et al. [37] HCN4 overexpression Global (Heterozygous, without doxycycline)	Isolated SAN cells: Regular firing pattern	Not reported	Isolated SAN cells: Firing rate normal	Adult mice (HZ): HR unchanged	Adult mice (HZ): HRV reduced
Kozasa et al. [37] HCN4 knockdown Global (Heterozygous, doxycycline-inducible)	Isolated SAN cells: Irregular firing pattern (quiescent cells excluded)	Not reported	Isolated SAN cells: Firing rate reduced	Adult mice (HZ): HR reduced	Adult mice (HZ): Bradycardia, sinus arrhythmia, HRV increased Chronotropic effect preserved
cAMP-insensitive HCN4 channels
Harzheim et al. [25] HCN4R669Q, knock-in, cAMP-insensitive Global	Isolated embryonic cardiomyocytes: Slow but regular firing pattern	Hyperpolarized Mutant: − 83 mV WT: − 74 mV	Isolated embryonic cardiomyocytes: Firing rate reduced	Isolated embryonic hearts: HR reduced Adult mice (HZ): HR unchanged	Embryonic lethality Chronotropic effect absent
Alig et al. [1] hHCN4-573X, transgenic, cAMP-insensitive Heart-specific Inducible (dox-withdrawal)	Isolated SAN cells: Heterogeneous firing patterns (quiescent, intermittent beating, arrhythmic)	Depolarized Mutant: − 51 mV WT: − 58 mV (quiescent cells excluded)	Spontaneously active SAN cells: Firing rate reduced	Adult mice: HR reduced	Bradycardia Chronotropic effect preserved
Fenske et al. [22] HCN4FEA, knock-in, cAMP-insensitive Global	Isolated SAN cells: Periodic changes between firing and nonfiring	Unchanged during firing Hyperpolarized during nonfiring	Isolated SAN cells: Normal rate during firing	Adult mice: HR reduced	Bradycardia, sinus dysrhythmia, escape arrhythmias Chronotropic effect preserved